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  • Surgical Pathology Criteria

    Extranodal Marginal Zone B Cell Lymphoma


    • Neoplasm composed primarily of small B lymphocytes frequently with moderately abundant pale cytoplasm (monocytoid cells) and a predilection for involvement of mucosal sites

    Alternate/Historical Names

    Diagnostic Criteria

    • Other than monocytoid cells, lymphoepithelial lesions, marginal zone involvement and follicular colonization, most of the findings are rather nonspecific for distinction from other small B lymphomas
    • Small to medium sized cells
      • Nuclei round or indented
      • Clumped chromatin
    • Cytoplasm inconspicuous to moderately abundant and pale (monocytoid)
    • Plasmacytoid differentiation frequent
      • Can be extensive, resembling plasmacytoma
      • Many head and neck plasmacytomas may actually be marginal zone lymphomas
    • May form lymphoepithelial lesions
      • Infiltration of non-neoplastic epithelium by lymphoma cells
        • Three or more lymphoid cells
        • Destruction of epithelium
          • Typically increased eosinophilia
      • Relatively specific finding if present
    • May involve marginal zones of reactive follicles
      • Cells in marginal zone frequently monocytoid
      • Infiltrate usually extends from marginal zone into adjacent regions
        • May become interfollicular
    • May show follicular colonization
      • Infiltration of germinal centers by lymphoma cells
      • Typically large cells
        • In spite of large cells, no worsening of prognosis
      • Relatively specific finding if present
    • Lacks specific markers of other small cell lymphomas
      • Negative to infrequent for CD23, bcl1, CD5, CD10
      • Positive for B lineage markers and bcl2
      • No specific positive immunologic marker
        • Immunologically, a diagnosis of exclusion
    • Preferentially involves epithelial organs or sites
      • Location not diagnostic as other lymphomas may involve the same sites
      • Same histologic and immunologic findings in lymph node or spleen is designated nodal or splenic marginal zone lymphoma
    • Transformation reported in 20% of cases
      • Either at diagnosis or subsequently
      • Usually large B cell lymphoma
      • Hodgkin lymphoma has been rarely reported
    • Immunoproliferative small intestinal disease variant produces only alpha heavy chains

    Yasodha Natkunam MD PhD
    Robert V Rouse MD
    Department of Pathology
    Stanford University School of Medicine
    Stanford CA 94305-5342

    Original posting:: October 11, 2006

    Variant: Immunoproliferative Small Intestinal Disease

    Definition of IPSID

    • Subtype of extranodal marginal zone lymphoma involving the small intestine, with alpha heavy chain production

    Alternate/Historical Names for IPSID

    • IPSID
    • Alpha heavy chain disease
    • Mediterranean lymphoma

    Diagnostic Criteria for IPSID

    • Lymphoplasmacytic infiltrate
      • Usually prominently plasmacytic
      • Lymphoepithelial lesions and follicular colonization may be prominent
    • Involves mucosa, may extend into submucosa
    • Mesenteric lymph node involvement common
    • May transform to large cell lymphoma
      • May retain plasmacytic differentiation
      • Typically forms tumor masses

    Immunologic Stains for IPSID

    • Alpha heavy chain positive
    • No light chain
    • Otherwise similar to usual marginal zone lymphoma

    Clinical Findings of IPSID

    • Predominantly Mediterranean in distribution
      • Also reported in South Africa
      • Sporadic reports in other sites
    • Predominantly young adults
    • Presents with diarrhea (steatorrhea) and weight loss
    • Alpha heavy chain may be detected in serum
    • An association with Campylobacter jejuni infection has been reported

    Supplemental studies

    Immunohistology and Flow Cytometry

    • B lineage 100%
    • Immunoglobulin light and heavy chains variably detectable
      • More frequent in plasmacytoid cases
    • CD23 8%
    • CD5 negative
    • CD43 35%
    • bcl1 negative
    • CD10 2%
    • bcl2 65-90%
    • bcl6 negative
    • Cases with transformation to diffuse large cell lymphoma maintain CD5 and CD10 negativity
    • CD138 can be extensive if plasmacytoid differentiation is prominent
    • bcl10 nuclear overexpression reported in cases with specific translocations
      • We do not find this stain reliable at this time
      • If present this would be an indication of resistance to antibiotic therapy
    • Immunoproliferative small intestinal disease variant
      • Alpha heavy chain positive
      • No light chain

    Genetic Study

    • t(11;18)(q21;q21)
      • 40% of gastric and lung cases
        • Less frequent in salivary and orbital cases
      • Low likelihood of large cell transformation
      • Not responsive to antibiotic therapy
      • PCR is currently the best test for this
        • FISH is not reliable
    • t(1;14)(p22;q32)
      • 5% of gastric and lung cases
      • Not responsive to antibiotic therapy
      • Low likelihood of large cell transformation
    • Trisomy 3
      • 60% of cases

    Differential Diagnosis

    Extranodal vs. Nodal vs. Splenic Marginal Zone Lymphomas

    • Extranodal involvement takes precedence in separation of the three types
      • Mixed types are designated as extranodal with nodal or splenic involvement
    • Nodal type must lack extranodal involvement
    • Splenic type must lack both extranodal and peripheral nodal involvement
      • Splenic hilar nodes may be involved
    • Genetic abnormalities are incompletely studied but support the above separation
      Extranodal Nodal Splenic
    7q21-32 loss rare rare 40%
    trisomy 3 60% rare 17%
    t(11;18) 25-50% rare 0%


    Small B Cell Lymphomas
      SLL/CLL Mantle Marginal Zone Lymphoplasmacytic Follicular
    CD23 85% 2% 8% 0-30% on immunohistology but up to 60% weak positive on flow 0-25%
    CD5 80% 80% 0% 5% 0%
    bcl1 2% 85% 0% 0% 0%
    CD10 0% 2% 2% 3% 85%
    CD43 80% 85% 35% 10-30% 7%
    bcl2 95% 95% 65-90% >50% 90%
    • CD23 staining refers to lymphoid staining
      • Follicular dendritic cells stain in many processes
    • bcl1
      • Blastic mantle cell lymphoma 100%
      • Hairy cell leukemia 41%
    • CD43 stains only 2% of splenic marginal zone lymphoma


    Extranodal Marginal Zone Lymphoma SLL/CLL
    Nodular pattern with prominent marginal zone Diffuse effacement
    Polymorphous cell population Uniform small round lymphocytes
    May have residual germinal centers Proliferation centers frequent
    CD23 8% CD23 85%
    CD5 negative CD5 80%
    CD43 35% CD43 80%
    Both may involve the GI tract and other mucosal sites


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Lymphoplasmacytic Lymphoma
    Enlarged marginal zone Diffuse effacement
    Pale monocytoid cells No monocytoid population
    • No useful distinguishing immunologic markers
    • Marginal zone lymphomas are frequently plasmacytoid; this combined with the lack of a definitive marker can make this distinction difficult
    • The distinction is sometimes suggested by the propensity to involve mucosal sites by extranodal marginal zone lymphoma


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Mantle Cell Lymphoma
    Enlarged marginal and mantle zones Enlarged mantle zone frequent
    Polymorphous population Uniform small lymphocytes
    bcl1 negative bcl1 85%
    CD25 negative CD25 30%
    CD5 negative CD5 80%
    CD43 35% (Splenic 2%) CD43 85%
    • Both may involve the GI tract and other mucosal sites in extranodal cases.
    • Enlarged marginal and mantle zones may be hard to distinguish


    Extranodal Marginal Zone Lymphoma Follicular Lymphoma
    Polymorphous population Uniform population of atypical small lymphocytes
    Centers of nodules may contain bcl2 negative residual germinal centers Centers of nodules composed of bcl2 positive small atypical lymphocytes
    Plasmacytoid differentiation frequent Plasmacytoid differentiation rare
    Lymphoepithelial lesions may be seen No lymphoepitelial lesions
    CD10 2% CD10 85%
    • Both may involve the GI tract and other mucosal sites
    • Both usually express bcl2 in the neoplastic cells
    • Cases with combined features are occasionally seen


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Mast Cell Disease
    B lineage markers positive B lineage markers negative
    Toluidine blue, Giemsa stains negative Toluidine blue, Giemsa stains positive
    CD117, tryptase immuno stains negative CD117, tryptase immuno stains positive
    Pale marginal zone cells may simulate mast cells


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Marginal Zone Hyperplasia
    Monocytoid cells may be prominent No monocytoid population
    Light chain monotypia variably demonstrable No monotypia
    Clonal Ig gene rearrangement No clonal rearrangement
    Coexpression of CD43 by B cells 35% No CD43 coexpression
    Sheets of B cells Distinct B and T cell zones


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma with Large Cell Transformation Sporadic Diffuse Large B Cell Lymphoma
    Prior or concurrent specimen with typical marginal zone lymphoma No evidence of typical marginal zone lymphoma
    CD5 negative CD5 10%
    CD10 2% CD10 25-50%
    bcl6 negative bcl6 60%
    Both may involve the GI tract and other mucosal sites


    Plasmacytoma / Myeloma Lymphoplasmacytic Lymphoma and Nodal, Extranodal and Splenic Marginal Zone Lymphomas
    Plasma cells may be pleomorphic or plasmablastic Plasma cell component usually not markedly atypical
    Uniform plasma cell morphology Plasma cells mixed with small lymphocytes
    IgG or IgA M component most common IgM or IgG M component most common
    CD20 often negative CD20 80%
    Uniformly CD138 positive Scattered CD138 positive cells
    Often CD56+, CD19-, CD45- CD56-, CD19+, CD45+

    Extranodal Marginal Zone Lymphoma Enteropathy Type T Cell Lymphoma
    Generally predominantly small cell pattern Wide variety of patterns
    B lineage T lineage
    Both may involve the GI tract


    • Mean age 60 years, rare before 30
      • Immunnoproliferative small intestinal disease variant usually young adults
    • Generally involves epithelial organs or sites
      • Head and neck
        • Salivary gland
        • Thyroid
        • Pharynx
        • Conjunctiva and lacrimal gland
          • Associated with Chlamydia species
            • Geographic variation in incidence reported
      • Gastrointestinal tract
        • Stomach
        • Intestines
      • Urinary tract
        • Bladder
        • Kidney
      • Skin
      • Breast
    • Frequently remains localized to an extranodal site
    • Recurrences frequently extranodal
    • Frequent clinical associations, depending upon location
      • Sjogren syndrome (salivary and lacrimal gland)
        • About 5% develop lymphoma
      • Hashimoto disease (thyroid)
        • About 1% develop lymphoma
      • Helicobacter pylori infection (stomach)
        • Eradication of Helicobacter can lead to remission
        • Cases that persist after anti-Helicobacter therapy may harbor specific translocations
    • Overall prognosis excellent
      • Indolent and slow to disseminate
      • No worsening of prognosis with dissemination
      • No worsening of prognosis with follicular colonization, even if by large cells
      • At some sites, cure by excision has been reported
      • Worse prognosis following transformation
    • Incidence
      • Marginal zone lymphomas of all types make up approximately 8% of lymphomas
      • 50% of gastric lymphomas
    • Geographic distribution
      • Gastric marginal zone lymphoma is increased in northern Italy
      • Immunoproliferative small intestinal disease is most common in Mediterranean zone and South Africa

    Grading / Staging / Report

    • While staging is linked to prognosis, it does not generally determine therapy
      • Therapy generally determined by clinical signs and symptoms
    • Pathologic staging is usually limited to bone marrow biopsy and biopsies of other sites to confirm clinical evidence of involvement

    Ann Arbor Staging System

    • Stage I
      • I if involvement of a single lymph node region
      • IE if involvement of a single extralymphatic organ or site
    • Stage II
      • II if two or more lymph node regions on same side of diaphragm
      • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
    • Stage III
      • III if Involvement of lymph node regions on both sides of the diphragm
      • IIIS if spleen involved
      • IIIE if extralymphatic site involved
    • Stage IV
      • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
    • Systemic Symptoms in 6 months preceding admission
      • Fever, night sweats, 10% weight loss
      • A = absent
      • B = present
    • Extranodal sites are also designated
      • M+ = marrow
      • L+ = lung
      • H+ = liver
      • P+ = pleura
      • O+ = bone
      • D+ = skin and subcutaneous tissue
    • Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

    The pathology report should contain the following information:

    • Diagnosis in the World Health Organization (WHO) classification
      • Equivalent diagnosis in other classifications used by relevant clinicians
    • Results of supplementary studies if performed
    • Relationship to other specimens from the same patient
    • Information relevant to staging if available
    • Report should address relevant associations such as Helicobacter, Hashimoto disease etc.
    • If present, comment on transformation



    Types of small B cell lymphoma

    Gastrointestinal tract lymphomas


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    • Hamilton SR, Aaltonen LA eds. Pathology and Genetics of Tumours of the Digestive System, World Health Organization Classification of Tumours 2000
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